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Franzè MS, Saitta C, Lombardo D, Musolino C, Caccamo G, Filomia R, Pitrone C, Cacciola I, Pollicino T, Raimondo G. Long-term virological and clinical evaluation of chronic hepatitis B patients under nucleos(t)ide analogues therapy. Clin Res Hepatol Gastroenterol 2025; 49:102566. [PMID: 40043798 DOI: 10.1016/j.clinre.2025.102566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/02/2025] [Indexed: 04/06/2025]
Abstract
INTRODUCTION AND OBJECTIVES Identifying hepatitis B virus (HBV) patients eligible for safe nucleos(t)ide analogues (NAs) discontinuation remains challenging. Discrepant data on combined HBV DNA and quantitative HBV surface antigen (qHBsAg) assessments are available. This study aimed to identify potential predictors for safe treatment discontinuation by evaluating clinical/virological outcomes in patients on long-term NA therapy. PATIENTS AND METHODS A retrospective cohort of 139 chronic hepatitis B (CHB) patients - who consecutively started Entecavir or Tenofovir from 2007 to 2011 - was evaluated. The study population was selected based on anti-HBe positivity, absence of prior antiviral treatment, absence of non-HBV-related liver diseases or hepatocellular carcinoma (HCC), and long-term clinical/ultrasonographic/laboratory evaluations post-NA initiation. Serum samples collected before starting NA (T0) and over ten years (T1-T10) were tested for HBV DNA and qHBsAg. RESULTS Twenty-two/139 (15.8 %) CHB patients (12 chronic hepatitis, 10 cirrhosis) met the inclusion criteria. All patients showed a significant decrease in liver stiffness values in the ten years of follow-up (p = 0.001), and no hepatic decompensation occurred. Three/22 (13.6 %) patients developed HCC. Ten/22 patients (45.5 %; group-A) had fluctuating HBV DNA, while other 10/22 (45.5 %; group-B) showed undetectable HBV DNA for 5-9 years with more significant qHBsAg decline (p = 0.04) than group-A. Two/22 (9.1 %) patients showed a critical qHBsAg decline up to seroconversion together with undetectable HBV DNA. CONCLUSIONS Persistent undetectable HBV DNA levels correlate with qHBsAg reduction and the potential HBsAg seroclearance, suggesting that long-term HBV DNA monitoring in NA-treated CHB patients might help identify candidates for treatment discontinuation.
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Affiliation(s)
- Maria Stella Franzè
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Carlo Saitta
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Daniele Lombardo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Cristina Musolino
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Gaia Caccamo
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Roberto Filomia
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Concetta Pitrone
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Irene Cacciola
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Teresa Pollicino
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Giovanni Raimondo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy.
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Liu TT, Xie MF, Liu X, Li RT, Bai Y, Zhang ZJ. Design, Synthesis, and Bioevaluation of Matrine Derivatives as Potential Anti-Hepatitis B Virus Agents. Biomolecules 2025; 15:436. [PMID: 40149972 PMCID: PMC11940400 DOI: 10.3390/biom15030436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/13/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025] Open
Abstract
Hepatitis B virus (HBV) is a causative reagent that frequently causes progressive liver diseases, leading to the development of acute hepatitis, chronic hepatitis, cirrhosis, and eventually hepatocellular carcinoma. Despite several antiviral drugs, including interferon-α and nucleotide derivatives, being approved for clinical treatment of HBV, critical issues remain unresolved, e.g., their low-to-moderate efficacy and adverse side effects, as well as resistant strains. In this study, twenty-three matrine derivatives were synthesized, and their antiviral effects against HBV were evaluated. Of these, eleven compounds inhibited HBeAg secretion significantly more than the positive control, lamivudine (3TC). Among the compounds synthesized in this study, compounds 4a and 4d had the most potent inhibitory activity, with IC50 value of 41.78 and 33.68 μM, respectively. Compounds 1h, 4a, and 4d were also subjected to molecular docking studies. These compounds inhibited viral gene expression and viral propagation in a cell culture model. Thus, we believe our compounds could serve as resource for antiviral drug development.
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Affiliation(s)
| | | | | | | | - Yao Bai
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; (T.-T.L.); (M.-F.X.); (X.L.); (R.-T.L.)
| | - Zhi-Jun Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; (T.-T.L.); (M.-F.X.); (X.L.); (R.-T.L.)
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3
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Hirode G, Janssen HLA. Reply to Wu and Zhang. Am J Gastroenterol 2025:00000434-990000000-01611. [PMID: 40029054 DOI: 10.14309/ajg.0000000000003342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Affiliation(s)
- Grishma Hirode
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- The Toronto Viral Hepatitis Care Network (VIRCAN), Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands
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Ji Y, Le Bert N, Lai-Hung Wong G, Douglas MW, Lee A, Zhu C, Wang B, Lv J, Li D, Tan Y, Ma H, Chen J, Chen X, Zhu Q, Yuen MF, Bertoletti A. The Impact of Hepatitis B Surface Antigen Reduction via Small Interfering RNA Treatment on Natural and Vaccine (BRII-179)-Induced Hepatitis B Virus-Specific Humoral and Cellular Immune Responses. Gastroenterology 2025:S0016-5085(25)00466-4. [PMID: 40043858 DOI: 10.1053/j.gastro.2025.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/17/2025] [Accepted: 02/10/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND & AIMS The impact of hepatitis B surface antigen (HBsAg) reduction from small interfering RNA (siRNA) treatments on hepatitis B virus (HBV)-specific immunity of individuals with chronic hepatitis B (CHB) has not been adequately analyzed in humans. We conducted a phase 2a study treating CHB participants with nine 4-weekly doses of HBV-targeted siRNA elebsiran (BRII-835), either alone (n = 10) or in combination with a virus-like particle-based therapeutic vaccine (BRII-179) containing Pre-S1, Pre-S2, and S antigens, coadministered with (n = 39) or without (n = 41) interferon alfa. METHODS We analyzed longitudinally for 72 weeks virologic, clinical, and immunologic parameters, including HBsAg, alanine aminotransferase, hepatitis B surface antibody (anti-HBs), the neutralizing activity of representative sera, and frequency and cytokine secretion ability of T cells specific for Pre-S1, Pre-S2, and S both directly ex vivo and after in vitro expansion. RESULTS Combination therapy with elebsiran and BRII-179 was well tolerated. Although no sustained HBsAg seroclearance or notable difference in mean HBsAg reduction at the group level was observed, we detected marked heterogeneity in immunologic responses among groups. HBsAg reduction mediated by siRNA alone was associated with minimal HBV-specific immune response recovery. In contrast, combination of elebsiran with BRII-179 induced a significant modification of immune responses demonstrated by anti-HBs antibody production and an expansion of interleukin 2-producing helper T cells specific for Pre-S1/Pre-S2 antigens only. Importantly, anti-HBs antibodies persisted at ≥100 IU/L in ∼40% of the participants for at least 32 weeks after combined treatment. Moreover, the neutralizing ability of the anti-HBs-positive sera was associated with HBsAg reduction. CONCLUSIONS siRNA-induced HBsAg reduction may contribute to the persistence and efficacy of the humoral arm of HBV-specific adaptive immunity in CHB participants receiving the therapeutic vaccine BRII-179. CLINICALTRIALS gov number: NCT04749368.
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Affiliation(s)
- Yun Ji
- Brii Biosciences, Inc, Durham, North Carolina
| | - Nina Le Bert
- Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Mark W Douglas
- Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, New South Wales, Australia
| | - Ariel Lee
- T Cell Diagnostics/Hyris Pte Ltd, Singapore
| | - Chong Zhu
- Brii Biosciences (Beijing) Co Ltd, Beijing, China
| | - Bing Wang
- Key Laboratory of Medical Molecular Virology, Ministry of Education, National Health Commission (MOE&NHC), Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianxiang Lv
- Brii Biosciences (Beijing) Co Ltd, Beijing, China
| | - Dong Li
- Brii Biosciences (Beijing) Co Ltd, Beijing, China
| | - Ying Tan
- Brii Biosciences (Beijing) Co Ltd, Beijing, China
| | - Haiyan Ma
- T Cell Diagnostics/Hyris Pte Ltd, Singapore
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology, Ministry of Education, National Health Commission (MOE&NHC), Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaofei Chen
- Brii Biosciences (Beijing) Co Ltd, Beijing, China
| | - Qing Zhu
- Brii Biosciences, Inc, Durham, North Carolina.
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Antonio Bertoletti
- Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore.
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Mak LY, Wooddell CI, Lenz O, Schluep T, Hamilton J, Davis HL, Mao X, Seto WK, Biermer M, Yuen MF. Long-term hepatitis B surface antigen response after finite treatment of ARC-520 or JNJ-3989. Gut 2025; 74:440-450. [PMID: 39266050 DOI: 10.1136/gutjnl-2024-333026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/29/2024] [Indexed: 09/14/2024]
Abstract
BACKGROUND AND AIMS RNA interference has been extensively explored in patients with chronic hepatitis B (CHB) infection. We aimed to characterise the long-term efficacy of small interfering RNA (siRNA) on hepatitis B surface antigen (HBsAg) suppression. METHODS We prospectively followed up participants with CHB who received siRNA, either ARC-520 or JNJ-73763989 (JNJ-3989), in combination with nucleoside analogue (NUC) in our centre. Participants enrolled included 15 receiving 4 monthly injections of ARC-520, 38 receiving 3 injections of JNJ-3989 at 1, 2 or 4 weekly intervals and 5 receiving placebo in previous clinical trials. Serial blood sampling was performed according to the original protocols and on completion every 24 weeks until last follow-up (LFU) with mean duration of 52.5 months. RESULTS Among the 53 NUC+siRNA-treated participants (mean age 46.8, baseline HBsAg 3.08 log, 83% previously on NUC, 34% hepatitis B e antigen+), the proportion of patients achieving HBsAg seroclearance or <100 IU/mL at LFU was 1.9% and 32.1%, respectively, compared with 0% and 0% for placebo. Among siRNA-recipients, 48.5% and 5.0% of those with HBsAg <100 IU/mL and >100 IU/mL at nadir or ≤24 weeks from last dose could maintain or achieve HBsAg <100 IU/mL at LFU, respectively. Compared with placebo recipients, siRNA-recipients demonstrated faster overall annual decline of HBsAg (0.08 vs 0.21 log IU/mL/year) contributed predominantly by changes in the first year. Age was negatively correlated with HBsAg reduction at LFU (r=-0.427, p=0.001). CONCLUSION Short-duration siRNA treatment suppressed HBsAg expression with a prolonged effect for up to 6 years in some participants.
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Affiliation(s)
- Lung Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Christine I Wooddell
- Arrowhead Madison, Arrowhead Pharmaceuticals Inc Madison Office, Madison, Wisconsin, USA
| | | | - Thomas Schluep
- Arrowhead Pharmaceuticals Inc, Pasadena, California, USA
| | - James Hamilton
- Arrowhead Pharmaceuticals Inc, Pasadena, California, USA
| | | | - Xianhua Mao
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | | | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
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Wu D, Kao JH, Piratvisuth T, Wang X, Kennedy PT, Otsuka M, Ahn SH, Tanaka Y, Wang G, Yuan Z, Li W, Lim YS, Niu J, Lu F, Zhang W, Gao Z, Kaewdech A, Han M, Yan W, Ren H, Hu P, Shu S, Kwo PY, Wang FS, Yuen MF, Ning Q. Update on the treatment navigation for functional cure of chronic hepatitis B: Expert consensus 2.0. Clin Mol Hepatol 2025; 31:S134-S164. [PMID: 39838828 PMCID: PMC11925436 DOI: 10.3350/cmh.2024.0780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 01/23/2025] Open
Abstract
As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.
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Affiliation(s)
- Di Wu
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Xiaojing Wang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Patrick T.F. Kennedy
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Academic Fields of Medicine, Dentistry, and Pharmaceutical Science, Okayama University, Okayama, Japan
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Guiqiang Wang
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Wenhui Li
- National Institute of Biological Sciences, Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Jilin, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiliang Gao
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Meifang Han
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Weiming Yan
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Sainan Shu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Paul Yien Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford University School of Medicine, Stanford, CA, USA
| | - Fu-sheng Wang
- Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine & State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
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Urbanek-Quaing M, Cornberg M. Editorial: Stopping NUCs-When to Restart NUCs for the Best Outcome? Aliment Pharmacol Ther 2025; 61:204-205. [PMID: 39499186 DOI: 10.1111/apt.18370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 10/18/2024] [Accepted: 10/18/2024] [Indexed: 11/07/2024]
Affiliation(s)
- Melanie Urbanek-Quaing
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence RESIST (EXC2155), Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence RESIST (EXC2155), Hannover Medical School, Hannover, Germany
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Lim SG, Teo AED, Chan ESY, Phyo WW, Chen DHY, Hargreaves CA. Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B Using HBsAg Thresholds: A Meta-Analysis and Meta-Regression. Clin Gastroenterol Hepatol 2024; 22:2403-2412. [PMID: 38871150 DOI: 10.1016/j.cgh.2024.05.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 04/30/2024] [Accepted: 05/28/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND AND AIMS Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression. METHODS We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up. RESULTS We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse. CONCLUSIONS While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.
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Affiliation(s)
- Seng Gee Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore.
| | - Ada Ee Der Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Edwin Shih-Yen Chan
- Singapore Clinical Research Institute, Consortium for Clinical Research and Innovation Singapore, Singapore; Cochrane Singapore, Singapore; Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore
| | - Wah Wah Phyo
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - David Hsing Yu Chen
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Carol Anne Hargreaves
- Data Analytics Consulting Centre, Faculty of Science, National University of Singapore, Singapore
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9
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Mak LY, Boettler T, Gill US. HBV Biomarkers and Their Role in Guiding Treatment Decisions. Semin Liver Dis 2024; 44:474-491. [PMID: 39442530 DOI: 10.1055/a-2448-4157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Over 300 million individuals worldwide are chronically infected with hepatitis B virus and at risk for progressive liver disease. Due to the lack of a therapy that reliably achieves viral elimination and the variability of liver disease progression, treatment decisions are guided by the degree of liver disease and viral biomarkers as the viral life-cycle is well characterized and largely conserved between individuals. In contrast, the immunological landscape is much more heterogeneous and diverse and the measurement of its components is less well standardized. Due to the lack of a universal and easily measurable set of biomarkers, clinical practice guidelines remain controversial, aiming for a balance between simplifying treatment decisions by reducing biomarker requirements and using all available biomarkers to avoid overtreatment of patients with low risk for disease progression. While approved therapies such as nucleos(t)ide analogs improve patient outcomes, the inability to achieve a complete cure highlights the need for novel therapies. Since no treatment candidate has demonstrated universal efficacy, biomarkers will remain important for treatment stratification. Here, we summarize the current knowledge on virological and immunological biomarkers with a specific focus on how they might be beneficial in guiding treatment decisions in chronic hepatitis B.
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Affiliation(s)
- Lung-Yi Mak
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, The Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tobias Boettler
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Upkar S Gill
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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10
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Hume SJ, Holmes JA, Thompson AJ. Individualizing the Approach to Stopping Nucleos(t)ide Analogs: Can We Use a Low HBsAg Threshold to Predict a High Chance of Functional Cure and Minimal Risk of Hepatic Decompensation? Am J Gastroenterol 2024; 119:1644. [PMID: 38619141 DOI: 10.14309/ajg.0000000000002766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Affiliation(s)
- Simon John Hume
- St Vincent's Hospital Melbourne, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital and Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Jacinta Alison Holmes
- St Vincent's Hospital Melbourne, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - Alexander James Thompson
- St Vincent's Hospital Melbourne, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
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11
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van Bömmel F, Berg T. Reply to: "A comment on `A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B'". J Hepatol 2024; 80:e230-e231. [PMID: 38110010 DOI: 10.1016/j.jhep.2023.11.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 12/20/2023]
Affiliation(s)
- Florian van Bömmel
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Liebigstrasse 20, 04103 Leipzig, Germany.
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Liebigstrasse 20, 04103 Leipzig, Germany
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12
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Liaw YF. Letter regarding "Hepatitis B core-related antigen dynamics and risk of subsequent clinical relapses after nucleos(t)ide analog cessation". Clin Mol Hepatol 2024; 30:269-271. [PMID: 38295765 PMCID: PMC11016499 DOI: 10.3350/cmh.2024.0064] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 01/29/2024] [Accepted: 01/31/2024] [Indexed: 04/13/2024] Open
Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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13
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Souleiman R, Cornberg M. [Diagnosis and treatment of viral hepatitis B and D in 2024]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2024; 65:296-307. [PMID: 38418664 DOI: 10.1007/s00108-024-01671-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/25/2024] [Indexed: 03/02/2024]
Abstract
Despite the availability of vaccines, hepatitis B remains a significant cause of fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. The increase in reported hepatitis B cases in Germany is attributed to factors such as immigration and the hepatitis B surface antigen (HBsAg) screening introduced in 2020 as part of health check-ups. The indication for treatment depends on various factors, including the level of hepatitis B virus (HBV) DNA and inflammatory activity. Nucleos(t)ide analogues are the preferred treatment option, but functional cure, defined as HBsAg loss, is rare. In principle, treatment with nucleos(t)ide analogues should usually be discontinued after loss of HBsAg, but can be stopped earlier under certain conditions and is currently the subject of ongoing research. Pregnancy and immunosuppression in the context of hepatitis B require special attention. In addition, a possible hepatitis D virus co-infection must always be taken into account, which is why every HBsAg-positive person should be tested for anti-HDV. Since 2020, the entry inhibitor bulevirtide has become a new treatment option alongside pegylated interferon alfa, which represents a significant advance in the treatment landscape.
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Affiliation(s)
- Roni Souleiman
- Klinik für Gastroenterologie, Hepatologie, Infektiologie, und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland
- Zentrum für Individualisierte Infektionsmedizin (CiiM), Hannover, Deutschland
- Partnerstandort Hannover-Braunschweig, Deutsches Zentrum für Infektionsforschung (DZIF), Hannover, Deutschland
| | - Markus Cornberg
- Klinik für Gastroenterologie, Hepatologie, Infektiologie, und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.
- Zentrum für Individualisierte Infektionsmedizin (CiiM), Hannover, Deutschland.
- Partnerstandort Hannover-Braunschweig, Deutsches Zentrum für Infektionsforschung (DZIF), Hannover, Deutschland.
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14
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Liu YC, Jeng WJ, Peng CW, Chien RN, Liaw YF. Higher end-of-treatment HBsAg levels is associated with later onset but not severe relapse in HBeAg-negative chronic hepatitis B patients stopping antivirals. Aliment Pharmacol Ther 2024; 59:762-773. [PMID: 38234285 DOI: 10.1111/apt.17880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/22/2023] [Accepted: 01/05/2024] [Indexed: 01/19/2024]
Abstract
BACKGROUND Quantitative hepatitis B surface antigen (qHBsAg) level at end-of-treatment (EOT) predict clinical relapse (CR) after nucleos(t)ide analogues (Nuc) in chronic hepatitis B(CHB) patients. It is unclear if higher EOT qHBsAg leads to earlier onset or more severe off-Nuc CR. AIM This large cohort study investigates the association between EOT qHBsAg and CR onset/severity. METHODS This study enrolled HBeAg-negative CHB patients who had achieved undetectable HBV DNA for over 1 year after receiving Nuc therapy before discontinuation. The EOT qHBsAg level was categorised into three groups: <100, 100-999, ≥1000 IU/mL. The study assessed the predictability of qHBsAg levels for CR, and analysed and compared the incidence, time to onset and severity of CR among these three groups. RESULTS Patients with higher EOT qHBsAg showed a higher incidence of CR (≥1000, 100-999, <100 IU/mL: 73%, 65%, and 38%, p < 0.01) but a later onset of CR (median time to CR: 35, 33 and 27 weeks, p < 0.01). The predictabilities of EOT qHBsAg for CR were greater in patients aged <50-year-old or with genotype C than in those aged ≥50-year-old or with genotype B. There's no correlation between EOT qHBsAg level and ALT folds at CR (Pearson correlation coefficient: r = -0.03, p = 0.35). EOT qHBsAg was neither a predictor for severe hepatitis flare nor a predictor for hepatic decompensation. CONCLUSIONS Predictability using EOT qHBsAg levels for CR differed in subgroups of age and genotypes. Higher EOT qHBsAg levels correlate with higher incidence but later onset of CR. No correlation between EOT qHBsAg and relapse severity was observed.
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Affiliation(s)
- Yen-Chun Liu
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chien-Wei Peng
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan
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15
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Jeng WJ, Chien RN, Chen YC, Lin CL, Wu CY, Liu YC, Peng CW, Su CW, Hsu CE, Liaw YF. Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis. Hepatology 2024; 79:690-703. [PMID: 37625144 DOI: 10.1097/hep.0000000000000575] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND AND AIMS Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Chih-Lang Lin
- College of Medicine, Chang Gung University, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Keelung Branch, Taiwan
| | - Chia-Ying Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chung-Wei Su
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Cheng-Er Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
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16
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Liaw YF. When to Stop Antiviral Therapy in HBeAg-Negative Patients with Chronic Hepatitis B? CURRENT HEPATOLOGY REPORTS 2024; 23:221-226. [DOI: 10.1007/s11901-024-00663-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/16/2024] [Indexed: 01/03/2025]
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17
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Lim SG, Tan YC. Additional Measures After Stopping Nucleoside Analogues in HbeAg-Negative Chronic Hepatitis B: Better But Not Enough. Gastroenterology 2024; 166:23-24. [PMID: 37832923 DOI: 10.1053/j.gastro.2023.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/15/2023]
Affiliation(s)
- Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Yong Chuan Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
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18
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Hsu YC, Tseng CH, Kao JH. Safety considerations for withdrawal of nucleos(t)ide analogues in patients with chronic hepatitis B: First, do no harm. Clin Mol Hepatol 2023; 29:869-890. [PMID: 36916171 PMCID: PMC10577354 DOI: 10.3350/cmh.2022.0420] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 02/19/2023] [Accepted: 03/13/2023] [Indexed: 03/16/2023] Open
Abstract
Nucleos(t)ide analogues (NA) are widely used to treat hepatitis B virus (HBV) infection, but they cannot eradicate the virus and treatment duration can be lifelong if the endpoint is set at seroclearance of the hepatitis B surface antigen (HBsAg). As an alternative strategy, finite NA therapy without the prerequisite of HBsAg seroclearance has been proposed to allow treatment cessation in patients with sustained undetectable HBV viremia for two to three years. However, reactivation of viral replication almost always follows NA withdrawal. Whereas HBV reactivation might facilitate HBsAg seroclearance in some, it could lead to serious acute flare-ups in a certain proportion of patients. Occurrence and consequences of NA withdrawal flares are complicated with various factors involving the virus, host, and treatment. Accurate risk prediction for severe flares following NA cessation is essential to ensure patient safety. The risks of life-threatening flares in patients who discontinued NA according to the stopping rules of current guidelines or local reimbursement policies have recently been quantitatively estimated in large-scale studies, which also provided empirical evidence to help identify vulnerable patients at risk of devastating outcomes. Moreover, risk predictors were further explored and validated to hopefully aid in patient selection and management. In this narrative review with a focus on patient safety, we summarize and discuss current literature on the incidence of severe flares following NA cessation, risk stratification for candidate selection, rules of posttreatment monitoring, and indications for treatment resumption. We also share our thoughts on the limitations of existing knowledge and suggestions for future research.
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Affiliation(s)
- Yao-Chun Hsu
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
- School of Medicine College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Internal Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Hao Tseng
- School of Medicine College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, E-Da Cancer Hospital, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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19
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Hirode G, Hansen BE, Chen CH, Su TH, Wong G, Seto WK, Van Hees S, Papatheodoridi M, Brakenhoff SM, Lens S, Choi HSJ, Chien RN, Feld JJ, Forns X, Sonneveld MJ, Papatheodoridis GV, Vanwolleghem T, Yuen MF, Chan HLY, Kao JH, Hsu YC, Cornberg M, Jeng WJ, Janssen HLA. Incidence of Hepatic Decompensation After Nucleos(t)ide Analog Withdrawal: Results From a Large, International, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study). Am J Gastroenterol 2023; 118:1601-1608. [PMID: 36719174 DOI: 10.14309/ajg.0000000000002203] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 12/27/2022] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Despite improvements in the management of chronic hepatitis B (CHB), risk of cirrhosis and hepatocellular carcinoma remains. While hepatitis B surface antigen loss is the optimal end point, safe discontinuation of nucleos(t)ide analog (NA) therapy is controversial because of the possibility of severe or fatal reactivation flares. METHODS This is a multicenter cohort study of virally suppressed, end-of-therapy (EOT) hepatitis B e antigen (HBeAg)-negative CHB patients who stopped NA therapy (n = 1,557). Survival analysis techniques were used to analyze off-therapy rates of hepatic decompensation and differences by patient characteristics. We also examined a subgroup of noncirrhotic patients with consolidation therapy of ≥12 months before cessation (n = 1,289). Hepatic decompensation was considered related to therapy cessation if diagnosed off therapy or within 6 months of starting retreatment. RESULTS Among the total cohort (11.8% diagnosed with cirrhosis, 84.2% start-of-therapy HBeAg-negative), 20 developed hepatic decompensation after NA cessation; 10 events were among the subgroup. The cumulative incidence of hepatic decompensation at 60 months off therapy among the total cohort and subgroup was 1.8% and 1.1%, respectively. The hepatic decompensation rate was higher among patients with cirrhosis (hazard ratio [HR] 5.08, P < 0.001) and start-of-therapy HBeAg-positive patients (HR 5.23, P < 0.001). This association between start-of-therapy HBeAg status and hepatic decompensation remained significant even among the subgroup (HR 10.5, P < 0.001). DISCUSSION Patients with cirrhosis and start-of-therapy HBeAg-positive patients should be carefully assessed before stopping NAs to prevent hepatic decompensation. Frequent monitoring of viral and host kinetics after cessation is crucial to determine patient outcome.
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Affiliation(s)
- Grishma Hirode
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- The Toronto Viral Hepatitis Care Network (VIRCAN), Toronto, Ontario, Canada
| | - Bettina E Hansen
- Department of Epidemiology, Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands
| | | | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Grace Wong
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Wai-Kay Seto
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, SAR, China
| | - Stijn Van Hees
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | | | - Sylvia M Brakenhoff
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Sabela Lens
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Taoyuan, Taiwan
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- The Toronto Viral Hepatitis Care Network (VIRCAN), Toronto, Ontario, Canada
| | - Xavier Forns
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | | | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Man-Fung Yuen
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, SAR, China
| | - Henry L Y Chan
- The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yao-Chun Hsu
- E-DaHospital/I-Shou University, Kaohsiung, Taiwan
| | - Markus Cornberg
- Department of Gastroenterology, Hepatolology and Endocrinology, Hannover Medical School, Germany; Centre for Individualized Infection Medicine (CiiM), Hannover, Germany
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Taoyuan, Taiwan
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
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20
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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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21
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Xie Y, Li M, Ou X, Zheng S, Gao Y, Xu X, Yang Y, Ma A, Li J, Nan Y, Zheng H, Liu J, Wei L, Feng B. Lower end of treatment HBsAg and HBcrAg were associated with HBsAg loss after nucleos(t)ide analog cessation. BMC Gastroenterol 2023; 23:224. [PMID: 37386460 PMCID: PMC10308768 DOI: 10.1186/s12876-023-02852-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND Since hepatitis B surface antigen (HBsAg) loss is rarely achieved with nucleos(t)ide analog (NA) treatment, most patients require life-long NA treatment. Previous studies have shown that some patients remain virologically responsive even after NA cessation. However, there is still controversy surrounding whether NA discontinuation increases the HBsAg loss rate. Therefore, this study aimed to assess the cumulative rate of HBsAg loss and identify the predictors of HBsAg loss after NA discontinuation. METHODS This multicenter prospective study included HBV e antigen (HBeAg)-positive patients without cirrhosis from 12 hospitals in China who met the inclusion criteria. The enrolled patients stopped NA and were followed up with clinical and laboratory assessments every 3 months for 24 months after NA cessation or until clinical relapse (CR) occurred. RESULTS Overall, 158 patients were classified into two groups. Group A included patients with HBsAg positivity at NA cessation (n = 139), and Group B included patients with HBsAg negativity at NA cessation (n = 19). In Group A, the 12-month and 24-month cumulative rates of HBsAg loss were4.3%and 9.4%, respectively. End of treatment (EOT) HBsAg (hazard ratio (HR) = 0.152, P < 0.001) and EOT hepatitis B core-related antigen (HBcrAg) (HR = 0.257, P = 0.001) were associated with HBsAg loss. The areas under the receiver operating characteristic curves for EOT HBsAg and HBcrAg levels were 0.952 (P < 0.001) and 0.765 (P < 0.001), respectively. Patients with EOT HBsAg ≤ 135 IU/mL (59.2% vs. 1.3%, P < 0.001) or HBcrAg ≤ 3.6 logU/mL (17% vs. 5.4%, P = 0.027) had a higher 24-month cumulative HBsAg loss rate. In Group B, none of the patients experienced virological relapse after NA cessation. Only 1 (5.3%) patient had HBsAg reversion. CONCLUSIONS EOT HBsAg ≤ 135 IU/mL or HBcrAg ≤ 3.6 logU/mL can be used to identify patients with a higher likelihood of HBsAg loss after NA cessation. Patients with HBsAg negativity after NA cessation have favorable clinical outcomes, and HBsAg loss was durable in most cases.
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Affiliation(s)
- Yandi Xie
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China
| | - Minghui Li
- Department of Hepatology Division, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Sujun Zheng
- Complicated Liver Diseases and Artificial Liver Treatment and Training Center, Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment and Research, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Yinjie Gao
- Department of Infectious Diseases, The Fifth Medical Center, General Hospital of PLA, Beijing, 100039, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Ying Yang
- Department of Infectious Diseases, The Second Hospital of Xingtai, Xingtai, Hebei, 054001, China
| | - Anlin Ma
- Department of Infectious Disease, Friendship Hospital, Beijing, 100029, China
| | - Jia Li
- Department of Liver Disease, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China
| | - Huanwei Zheng
- Department of Liver Disease, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, 050021, China
| | - Juan Liu
- Research Center for Technologies in Nucleic Acid-Based Diagnostics, Changsha, Hunan, 410205, China
| | - Lai Wei
- Department of Hepatopancreatobiliary Disease, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Bo Feng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China.
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22
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Mak LY, Hui RWH, Cheung KS, Fung J, Seto WK, Yuen MF. Advances in determining new treatments for hepatitis B infection by utilizing existing and novel biomarkers. Expert Opin Drug Discov 2023; 18:401-416. [PMID: 36943183 DOI: 10.1080/17460441.2023.2192920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
INTRODUCTION Chronic hepatitis B (CHB) infection is a major global health threat and accounts for significant liver-related morbidity and mortality. An improved understanding of how hepatitis B virus (HBV) interacts with the host immune system allows the discovery of novel biomarkers and new treatment options. Viral biomarkers including hepatitis B surface antigen (HBsAg) and newer ones like HBV RNA and hepatitis B core-related antigen appear to be useful to select patients who are likely to benefit from cessation of long-term antiviral therapy. These markers can also help to confirm target engagement for novel compounds, and efficacy in HBsAg reduction and seroclearance is deemed essential as this is how the current treatment endpoint of functional cure is defined. AREAS COVERED In this review, the authors discuss the current standard of care and the gaps between such standard and the ideal goals for treatment in CHB. The authors highlight novel viral and immunological biomarkers that are potentially useful to evaluate treatment response. Novel treatment approaches in relation to these novel biomarkers are also evaluated. EXPERT OPINION Novel serum viral biomarkers and immunological markers are indispensable in the HBV functional cure program. These will likely become part of standard monitoring soon.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
| | - Ka-Shing Cheung
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
| | - James Fung
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong
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Emerging Therapies for Chronic Hepatitis B and the Potential for a Functional Cure. Drugs 2023; 83:367-388. [PMID: 36906663 DOI: 10.1007/s40265-023-01843-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2023] [Indexed: 03/13/2023]
Abstract
Worldwide, an estimated 296 million people are living with chronic hepatitis B virus (HBV) infection, with a significant risk of morbidity and mortality. Current therapy with pegylated interferon (Peg-IFN) and indefinite or finite therapy with nucleoside/nucleotide analogues (Nucs) are effective in HBV suppression, hepatitis resolution, and prevention of disease progression. However, few achieve hepatitis B surface antigen (HBsAg) loss (functional cure), and relapse often occurs after the end of therapy (EOT) because these agents have no direct effect on durable template: covalently closed circular DNA (cccDNA) and integrated HBV DNA. Hepatitis B surface antigen loss rate increases slightly by adding or switching to Peg-IFN in Nuc-treated patients and this loss rate greatly increases up to 39% in 5 years with finite Nuc therapy with currently available Nuc(s). For this, great effort has been made to develop novel direct-acting antivirals (DAAs) and immunomodulators. Among the DAAs, entry inhibitors and capsid assembly modulators have little effect on reducing HBsAg levels; small interfering RNA, antisense oligonucleotides, and nucleic acid polymers in combination with Peg-IFN and Nuc may reduce HBsAg levels significantly, even a rate of HBsAg loss sustained for > 24 weeks after EOT up to 40%. Novel immunomodulators, including T-cell receptor agonists, check-point inhibitors, therapeutic vaccines, and monoclonal antibodies may restore HBV-specific T-cell response but not sustained HBsAg loss. The safety issues and the durability of HBsAg loss warrant further investigation. Combining agents of different classes has the potential to enhance HBsAg loss. Compounds directly targeting cccDNA would be more effective but are still in the early stage of development. More effort is required to achieve this goal.
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Durantel D. Therapies against chronic hepatitis B infections: The times they are a-changin', but the changing is slow! Antiviral Res 2023; 210:105515. [PMID: 36603773 DOI: 10.1016/j.antiviral.2022.105515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 01/04/2023]
Abstract
PREAMBULAR NOTA BENE As a tribute to Dr Mike Bray, the following review of literature willbe mainly based on published data andconcepts, but will also contain my personal views, and in this respect could be more considered as a bioassay. Even though a cost-effective and excellent prophylactic vaccine exists since many years to protect against hepatitis B virus (HBV) infection, academic-researcher/drug-developers/stakeholders are still busy with the R&D of novel therapies that could eventually have an impact on its worldwide incidence. The Taiwanese experience have univocally demonstrated the effectiveness of constrained national HBV prophylactic vaccination programs to prevent the most dramatic HBV-induced end-stage liver disease, which is hepatocellular carcinoma; but yet the number of individuals chronically infected with the virus, for whom the existing prophylactic vaccine is no longer useful, remains high, with around 300 million individuals around the globe. In this review/bioassay, recent findings and novel concepts on prospective therapies against HBV infections will be discussed; yet it does not have the pretention to be exhaustive, as "pure immunotherapeutic concepts" will be mainly let aside (or referred to other reviews) due to a lack of expertise of this writer, but also due to the lack of, or incremental, positive results in clinical trials as-off today with these approaches.
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Affiliation(s)
- David Durantel
- Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, UMR_5308 CNRS-Université de Lyon (UCBL1), ENS de Lyon, Lyon, 69007, France.
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Chen CH, Jeng WJ, Hu TH, Liu YC, Wang JH, Hung CH, Lu SN, Chien RN. HBV relapse rates in patients who discontinue tenofovir disoproxil fumarate with or without switching to tenofovir alafenamide. Dig Liver Dis 2023; 55:771-777. [PMID: 36737315 DOI: 10.1016/j.dld.2023.01.154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 01/16/2023] [Accepted: 01/19/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS The incidence and relapse pattern in patients stopping tenofovir alafenamide (TAF), a prodrug of tenofovir which is more concentrated in hepatocytes, is unknown. METHODS HBeAg-negative CHB patients stopping tenofovir disoproxil fumarate (TDF) (off-TDF) or who had switched to TAF more than 3 months before discontinuation (off-TAF) were recruited. The propensity score-matching method (PSM) was used, creating a ratio of 1:3 between the off-TAF versus the off-TDF groups to adjust for associated factors. RESULTS After PSM, 180 off-TDF and 60 off-TAF patients were analyzed. The cumulative rates of virological and clinical relapse at 52 weeks were 75.1% and 58.5% respectively in the off-TDF group and 91.1% and 61.6% in the off-TAF group. Patients in the off-TAF group had significantly higher rates of virological relapse than those in the off-TDF group (p = 0.021), but not clinical relapse (p = 0.785). Multivariate cox regression analysis showed that off-TAF group was an independent factor for virological relapse, but not clinical relapse. Severity of clinical relapse and hepatic decompensation rate were comparable between off-TDF and off-TAF groups CONCLUSIONS: The off-TAF group had a higher virological relapse rate than the off-TDF group. The difference in clinical relapse pattern and severity was not clinically important between the two groups.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan.
| | - Wen-Juei Jeng
- Division of Hepatogastroenterology, Department of Internal Medicine, Linkuo Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Yen-Chun Liu
- Division of Hepatogastroenterology, Department of Internal Medicine, Linkuo Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Rong-Nan Chien
- Division of Hepatogastroenterology, Department of Internal Medicine, Linkuo Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
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Mak LY, Seto WK, Yuen MF. Correspondence on Editorial regarding "HBV pgRNA and HBcrAg reductions at week 4 predict favourable HBsAg response upon long-term nucleos(t)ide analogue in CHB". Clin Mol Hepatol 2023; 29:191-193. [PMID: 36417889 PMCID: PMC9845668 DOI: 10.3350/cmh.2022.0410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong,Corresponding author : Man-Fung Yuen Department of Medicine, The University of Hong Kong, Pokfulam Road, Hong Kong Tel: +852-22553984, Fax: +852-28162863, E-mail:
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Ciliatoside A, isolated from Peristrophe japonica, inhibits HBsAg expression and cccDNA transcription by inducing autophagy. Antiviral Res 2023; 209:105482. [PMID: 36496141 DOI: 10.1016/j.antiviral.2022.105482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/30/2022] [Accepted: 12/04/2022] [Indexed: 12/13/2022]
Abstract
Hepatitis B surface antigen (HBsAg) loss and seroconversion are considered as an end point of a functional cure. Therefore, it is crucial to find new agents which could efficiently decrease HBsAg. Traditional herbal plants have been considered as an important source of new hepatitis B drugs development for their extensive use in antimicrobial and anti-inflammation. In this study, Peristrophe japonica, which could remarkably reduce HBsAg in the supernatant of HepG2.2.15 cells, was screened out for further extraction. Here, an active ethyl acetate fraction of Peristrophe japonica containing 34 sub-fractions was extracted. Subsequently, the monomeric compound Ciliatoside A was isolated and identified as a potential antiviral reagent with low cytotoxicity from Fraction 30. Ciliatoside A exhibited strong inhibition on intracellular and circulating HBsAg and HBV RNAs in HBV-infected cells and an HBV recombinant-cccDNA mouse model. The mechanistic study revealed that Ciliatoside A exhibited a potent anti-HBV effect through inducing autophagy-lysosomal pathway to autophagic degradation of HBc by activating AMPK-ULK1 axis and inhibiting mTOR activation. In summary, we have identified a novel antiviral compound Ciliatoside A isolated from Peristrophe japonica. This study may provide important direction and new ideas for the discovery of hepatitis B cure drugs.
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Mak LY, Wong D, Kuchta A, Hilfiker M, Hamilton A, Chow N, Mao X, Seto WK, Yuen MF. Hepatitis B virus pre-genomic RNA and hepatitis B core-related antigen reductions at week 4 predict favourable hepatitis B surface antigen response upon long-term nucleos(t)ide analogue in chronic hepatitis B. Clin Mol Hepatol 2023; 29:146-162. [PMID: 35989092 PMCID: PMC9845664 DOI: 10.3350/cmh.2022.0172] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/12/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND/AIMS We investigated the dynamics of serum HBV pre-genomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) in patients receiving nucleos(t)ide analogues (NAs) and their predictability for favourable suppression of serum hepatitis B surface antigen (HBsAg). METHODS Serum viral biomarkers were measured at baseline, weeks 4, 12, 24, 36, and 48 of treatment. Patients were followed up thereafter and serum HBsAg level was measured at end of follow-up (EOFU). Favourable HBsAg response (FHR) was defined as ≤100 IU/mL or HBsAg seroclearance upon EOFU. RESULTS Twenty-eight hepatitis B e antigen (HBeAg)-positive and 36 HBeAg-negative patients (median, 38.2 years old; 71.9% male) were recruited with median follow-up duration of 17.1 years (interquartile range, 12.8-18.2). For the entire cohort, 22/64 (34.4%) achieved FHR. For HBeAg-positive patients, serum HBV pgRNA decline at week 4 was significantly greater for patients with FHR compared to non-FHR (5.49 vs. 4.32 log copies/mL, respectively; P=0.016). The area under the receiver-operating-characteristic curve (AUROC) for week 4 HBV pgRNA reduction to predict FHR in HBeAg-positive patients was 0.825 (95% confidence interval [CI], 0.661-0.989). For HBeAg-negative patients, instead of increase in serum HBcrAg in non-FHR patients, FHR patients had median reduction in HBcrAg at week 4 (increment of 1.75 vs. reduction of 2.98 log U/mL; P=0.023). The AUROC for week 4 change of HBcrAg to predict FHR in HBeAg-negative patients was 0.789 (95% CI, 0.596-0.982). CONCLUSION Early on-treatment changes of serum HBV pgRNA and HBcrAg at 4 weeks predict HBsAg seroclearance or ≤100 IU/mL in NA-treated CHB patients upon long-term FU.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Danny Wong
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | | | | | | | - Ning Chow
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - XianHua Mao
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Wai Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong,Corresponding author : Man-Fung Yuen Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Pokfulam Road, Hong Kong Tel: +852-22553984, Fax: +852-28162863, E-mail:
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong,Corresponding author : Man-Fung Yuen Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Pokfulam Road, Hong Kong Tel: +852-22553984, Fax: +852-28162863, E-mail:
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Peng CW, Jeng WJ, Yang HI, Liu YC, Chien RN, Liaw YF. A switch from tenofovir to entecavir prior to hepatitis B treatment cessation is associated with a reduced risk of off-therapy relapse: An observational study. J Gastroenterol Hepatol 2022; 37:2164-2172. [PMID: 35869752 DOI: 10.1111/jgh.15966] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM In HBeAg negative chronic hepatitis B (CHB) patients, clinical relapse (CR) occurs more frequently, much earlier and often more severely after stopping tenofovir (TDF) and other nucleos(t)ide analogues (Nucs) than after stopping entecavir (ETV). It is unknown whether off-Nuc hepatitis flare can be alleviated by switching from one Nuc to another. METHODS HBeAg-negative CHB patients who had stopped Nuc according to the APASL stopping rule and had been followed-up for > 48 weeks after Nuc cessation were recruited. Patients were classified as four groups: ETV monotherapy (mono-ETV), TDF monotherapy (mono-TDF), switched to ETV (switch-ETV), and switched to TDF (switch-TDF). Both switch groups had switched to the replacement Nuc > 12 weeks prior to end of therapy. Propensity score matching (PSM) was performed to minimize confounders among groups. Cox regression analysis was used to identify risks factors for off-Nuc CR and flares. RESULTS A total of 1309 patients (1022 mono-ETV, 219 mono-TDF, 40 switch-ETV and 28 switch-TDF) were enrolled. The median time to CR was 39, 13, 38 and 14 weeks in mono-ETV, mono-TDF, switch-ETV and switch-TDF respectively (P < 0.001). After PSM, the mono-ETV (adjusted HR: 0.39, P < 0.001) and switch-ETV patients (adjusted HR: 0.41, P = 0.003) had both significantly later occurrence and lower rates of CR and flare. CONCLUSION In summary, the incidence and timing of CR was determined by ETV or TDF in the last 3 months prior to end of treatment. Patients treated with non-ETV-Nuc switched to ETV > 12 weeks before end of the original Nuc therapy may reduce/defer CR.
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Affiliation(s)
- Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hwai-I Yang
- Genomic Research Center, Academia Sinica, Taipei, Taiwan
| | - Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan
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Liaw YF. Perspectives on current controversial issues in the management of chronic HBV infection. J Gastroenterol 2022; 57:828-837. [PMID: 36053366 DOI: 10.1007/s00535-022-01918-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/18/2022] [Indexed: 02/04/2023]
Abstract
Clinical and basic research in the past decades has achieved consensus in the understanding of chronic hepatitis B virus (HBV) infection and the management of chronic hepatitis B and HBV-cirrhosis. However, debatable challenges to the existing consensus in the concept and/or definitions have emerged. These include (1). alanine aminotransferase upper limit of normal: traditional laboratory-defined vs fixed; (2). nomenclature for phases of chronic HBV infection: classical vs EASL proposal; (3). indication of antiviral therapy: to treat patients vs to treat HBV; (4). finite vs indefinite long-term antiviral therapy: A. finite therapy in HBV-cirrhosis; B. retreatment decision: biochemical markers vs HBsAg/ALT kinetics. The pros and cons of these controversial issues were reviewed, assessed, and discussed in depth based on relevant lines of scientific evidence, intended to clarify or solve these controversial issues.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199, Tung Hwa North Road, Taipei, 105, Taiwan.
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Papatheodoridi M, Papachristou E, Moschidis Z, Hadziyannis E, Rigopoulou E, Zachou K, Villeret F, Magiorkinis G, Lyberopoulou A, Gatselis N, Vlachogiannakos I, Manolakopoulos S, Dalekos GN, Zoulim F, Paraskevis D, Papatheodoridis GV. Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy. J Viral Hepat 2022; 29:948-957. [PMID: 35789515 DOI: 10.1111/jvh.13729] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/13/2022] [Accepted: 06/20/2022] [Indexed: 12/30/2022]
Abstract
HBV RNA is considered as a promising predictor in patients who discontinue nucleos(t)ide analogues (NAs). We determined HBV RNA levels in non-cirrhotic HBeAg-negative patients who discontinued NAs and assessed their predictability for 12-month outcomes. Fifty-seven patients of DARING-B study were included. HBV RNA levels were determined in stored monthly serum samples drawn at 0-3 months after end of therapy (EOT). Other markers previously determined in the same cohort including hepatitis B core-related antigen (HBcrAg) were also assessed. HBV RNA at EOT was detectable in 7% of patients, who developed virological/clinical relapse and required retreatment at month 2; in patients with undetectable EOT HBV RNA, 12-month cumulative rates of virological relapse, clinical relapse and retreatment were 68%, 28% and 21%, respectively (p ≤ 0.008). HBV RNA at month-1 after EOT was detectable in 19% of patients being associated with higher probability only of virological relapse (p = 0.001). HBV RNA levels correlated significantly to HBV DNA, HBcrAg, ALT and interferon-induced protein-10, but not HBsAg levels. Combined EOT HBV RNA and HBcrAg detection and/or HBsAg >1000 IU/ml was associated only with higher probability of retreatment having higher sensitivity and lower specificity than HBV RNA alone. In conclusion, serum HBV RNA is detectable in a minority of non-cirrhotic HBeAg-negative patients under effective long-term NAs therapy offering low sensitivity but 100% specificity for early retreatment due to severe clinical relapses after NA discontinuation. The combinations of EOT HBV RNA with HBcrAg and/or high HBsAg levels increase sensitivity but decrease specificity for prediction of retreatment after NAs withdrawal.
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Affiliation(s)
- Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.,Institute of Liver and Digestive Health, University College of London, London, UK
| | - Eleni Papachristou
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Zissis Moschidis
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Emilia Hadziyannis
- 2nd Department of Internal Medicine, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Hippokratio", Athens, Greece
| | - Eirini Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | | | - Gkikas Magiorkinis
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Ioannis Vlachogiannakos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Spilios Manolakopoulos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Fabien Zoulim
- INSERM U1052 - Cancer Research Center of Lyon (CRCL), Lyon, France
| | - Dimitrios Paraskevis
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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Liaw YF. Hepatitis B flare: the good, the bad and the ugly. Expert Rev Gastroenterol Hepatol 2022; 16:1043-1051. [PMID: 36476208 DOI: 10.1080/17474124.2022.2156338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Hepatitis B flare, defined as an event of abrupt ALT elevation to >5x ULN, is a frequent episode during the natural course or during/after antiviral therapy of chronic HBV infection, in both HBeAg-positive and HBeAg-negative patients with chronic hepatitis B or liver cirrhosis. AREAS COVERED The definition, pathogenesis, clinical presentation, and management of hepatitis B flares in the published literature were reviewed. Hepatitis B flares have been considered as a result of the robust immune response of the patient to an upsurging HBV/HBV-antigen(s). 'Host-dominating flares,' reflect effective immune response, may resolve with ALT normalization and decline of HBV/ antigen(s). Contradictorily, 'virus-dominating flares,' reflect ineffective immune response, are usually followed by persistent/intermittent hepatitis and may even develop hepatic decompensation/failure. EXPERT OPINION Not all hepatitis B flares require antiviral therapy, and close observation with combined HBsAg/ALT kinetics along the ascending ALT during hepatitis flare may differentiate hepatitis flares for an appropriate treatment/retreatment decision. More studies are needed to verify this proposal. Further immunologic studies using multiple samples during hepatitis B flare are important to clarify the precise underlying mechanisms as the basis for further improvement in the management of hepatitis flare.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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Hirode G, Janssen HLA. Reply. Gastroenterology 2022; 163:779-780. [PMID: 35598630 DOI: 10.1053/j.gastro.2022.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 05/09/2022] [Indexed: 12/02/2022]
Affiliation(s)
- Grishma Hirode
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada, and, Institute of Medical Science, University of Toronto, Toronto, Canada, and, The Toronto Viral Hepatitis Care Network (VIRCAN), Toronto, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada, and, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherlands
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Chang ML, Chien RN, Liaw YF. Evidence-Based Management of Oral Nucleos(t)ide Analogue Withdrawal in Virally Suppressed Patients with Chronic HBV Infection. CURRENT HEPATOLOGY REPORTS 2022; 21:52-58. [DOI: 10.1007/s11901-022-00587-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/11/2022] [Indexed: 01/02/2025]
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Liu YC, Jeng WJ, Peng CW, Chien RN, Liaw YF. The Role of Off-Therapy Viral Kinetics in the Timing and Severity of Flares in Hepatitis B e Antigen-Negative Patients. Clin Gastroenterol Hepatol 2022; 21:1533-1541.e11. [PMID: 36038130 DOI: 10.1016/j.cgh.2022.08.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatitis B flare occurs earlier and is more severe in patients stopping tenofovir (TDF) compared with entecavir (ETV). This study investigated relationship between hepatitis B virus (HBV) kinetics, onset timing, and the severity of flares. METHODS Hepatitis B e antigen-negative chronic hepatitis B patients who developed off-ETV or off-TDF hepatitis flare were recruited. Their HBV kinetics and the severity of flares were compared between patients with early (<6 months) and late (between 6 and 24 months) flares. Propensity score matching was performed at 1:1 adjusting for age, sex, cirrhosis, and end-of-treatment (EOT) hepatitis B surface antigen between off-ETV and off-TDF flares. RESULTS After propensity score matching, 76% and 15% of each 107 off-TDF and off-ETV patients, respectively, developed early flare. A much steeper HBV DNA upsurge (ΔHBV DNA/month) was observed in off-TDF than off-ETV flares (2.12 vs 0.73 log10 IU/mL; P < .01). Greater ΔHBV DNA/month correlated with earlier timing and higher peak alanine aminotransferase levels of flares. ΔHBV DNA/month ≥2.5 log10 IU/mL was an independent factor for severe off-TDF flare, and ≥1 log10 IU/mL was a predictor for severe off-ETV flares. CONCLUSIONS Greater HBV DNA upsurge rate (ΔHBV DNA/month) ≥1 log10 IU/mL is a key factor for an earlier onset and more severe flare. More frequent ΔHBV DNA/month ≥1 log10 IU/mL in off-TDF than off-ETV flares may explain why off-TDF flare mostly occurred early and was more severe. More stringent monitoring in those with ΔHBV DNA/month ≥1 log10 IU/mL at flare, especially ≥2.5 log10 IU/mL in early off-TDF flares, is important for timely retreatment to prevent decompensation.
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Affiliation(s)
- Yen-Chun Liu
- College of Medicine, Chang Gung University, Taipei, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Chien-Wei Peng
- College of Medicine, Chang Gung University, Taipei, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Taiwan.
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Jindal A. Severity of Hepatitis B Relapse After Cessation of Nucleos(t)ide Analog: Need a Closer Look! Clin Gastroenterol Hepatol 2022; 20:1885-1886. [PMID: 34508869 DOI: 10.1016/j.cgh.2021.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 09/05/2021] [Indexed: 02/07/2023]
Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Evidence for a Hepatitis B Virus Short RNA Fragment Directly Targeting the Cellular RRM2 Gene. Cells 2022; 11:cells11142248. [PMID: 35883690 PMCID: PMC9318981 DOI: 10.3390/cells11142248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/14/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022] Open
Abstract
The hepatitis B virus (HBV) is one of the smallest but most highly infectious human pathogens. With a DNA genome of only 3.2 kb and only four genes, HBV successfully completes its life cycle by using intricate processes to hijack the host machinery. HBV infects non-dividing liver cells in which dNTPs are limited. As a DNA virus, HBV requires dNTPs for its replication. HBV induces the ATR-mediated cellular DNA damage response pathway to overcome this constraint. This pathway upregulates R2 (RRM2) expression in generating an active RNR holoenzyme catalyzing de novo dNTP synthesis. Previously we reported that ERE, a small RNA fragment within the HBx ORF, is sufficient to induce R2 upregulation. Interestingly, there is high sequence similarity between ERE and a region within the R2 5′UTR that we named R2-box. Here, we established a mutant cell line in the R2-box region of the R2 gene using CRISPR-Cas9 technology to investigate the R2 regulation by ERE. This cell line expresses a much lower R2 level than the parental cell line. Interestingly, the HBV infection and life cycle were severely impaired. These cells became permissive to HBV infection upon ectopically R2 expression. These results validate the requirement of the R2 gene expression for HBV replication. Remarkably, the R2-box mutated cells became ERE refractory, suggesting that the homology region between ERE and R2 gene is critical for ERE-mediated R2 upregulation. Thus, along with the induction of the ATR pathway of the DNA damage response, ERE might also directly target the R2 gene via the R2-box.
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Fung S, Choi HSJ, Gehring A, Janssen HLA. Getting to HBV cure: The promising paths forward. Hepatology 2022; 76:233-250. [PMID: 34990029 DOI: 10.1002/hep.32314] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
Chronic HBV infection is a global public health burden estimated to impact nearly 300 million persons worldwide. Despite the advent of potent antiviral agents that effectively suppress viral replication, HBV cure remains difficult to achieve because of the persistence of covalently closed circular DNA (cccDNA), HBV-DNA integration into the host genome, and impaired immune response. Indefinite treatment is necessary for most patients to maintain level of viral suppression. The success of direct-acting antivirals (DAAs) for hepatitis C treatment has rejuvenated the search for a cure for chronic hepatitis B (CHB), though an HBV cure likely requires an additional layer: immunomodulators for restoration of robust immune responses. DAAs such as entry inhibitors, capsid assembly modulators, inhibitors of subviral particle release, cccDNA silencers, and RNA interference molecules have reached clinical development. Immunomodulators, namely innate immunomodulators (Toll-like receptor agonists), therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also progressing toward clinical development. The future of the HBV cure possibly lies in triple combination therapies with concerted action on replication inhibition, antigen reduction, and immune stimulation. Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates. This review gives an overview of the current therapies for CHB, HBV biomarkers used to evaluate treatment response, and development of DAAs and immune-targeting drugs and discusses the limitations and unanswered questions on the journey to an HBV cure.
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Affiliation(s)
- Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Adam Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
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Broquetas T, Carrión JA. Current Perspectives on Nucleos(t)ide Analogue Therapy for the Long-Term Treatment of Hepatitis B Virus. Hepat Med 2022; 14:87-100. [PMID: 35936810 PMCID: PMC9346298 DOI: 10.2147/hmer.s291976] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/12/2022] [Indexed: 01/27/2023] Open
Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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Liao G, Liu Z, Xia M, Chen H, Wu H, Li B, Yu T, Cai S, Zhang X, Peng J. Soluble Programmed Cell Death-1 is a Novel Predictor of HBsAg Loss in Chronic Hepatitis B Patients When Long-Term Nucleos(t)ide Analog Treatment is Discontinued. Infect Drug Resist 2022; 15:2347-2357. [PMID: 35517900 PMCID: PMC9065130 DOI: 10.2147/idr.s360202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 04/23/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Guichan Liao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Ziying Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Muye Xia
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Hongjie Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Houji Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Bing Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Tao Yu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Shaohang Cai
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- Correspondence: Jie Peng, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Tel +86 20 6278 7428, Fax +86 20 8771 9653, Email
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Luo M, Zhou B, Hou J, Jiang D. Biomarkers for predicting nucleos(t)ide analogs discontinuation and hepatitis B virus recurrence after drug withdrawal in chronic hepatitis B patients. Hepatol Res 2022; 52:337-351. [PMID: 35089634 DOI: 10.1111/hepr.13749] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/22/2021] [Accepted: 01/20/2022] [Indexed: 12/11/2022]
Abstract
AIM To summarize HBV-related biomarkers predicting nucleos(t)ide analogs (NAs) discontinuation and hepatitis B virus (HBV) recurrence after drug withdrawal in chronic hepatitis B (CHB) patients, providing references for clinical medication, so as to manage CHB patients more scientifically. METHODS Related pieces of literature were retrieved in PubMed and the results were sorted out. We then analyzed and summarized these articles. RESULTS We found that HBV related biomarkers maybe could predict NAs withdrawal safely and the possibility of relapse after treatment cessation, including hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), HBV DNA, HBV RNA, pregenomic-RNA (pgRNA), hepatitis B core-related antigen (HBcrAg), hepatitis B core antibody (anti-HBc), and models containing several indicators for predicting the effectiveness of treatment. CONCLUSIONS HBV DNA, HBV RNA, pgRNA, HBcrAg, anti-HBc, as well as the prediction models formed by several biomarkers could predict the safe discontinuation of NAs before HBsAg loss and recurrence.
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Affiliation(s)
- Mengqi Luo
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Deke Jiang
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Liaw YF, Chien RN. Finite nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B: From an "option" to an "active recommendation". Kaohsiung J Med Sci 2022; 38:295-301. [PMID: 35262284 DOI: 10.1002/kjm2.12518] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 01/27/2022] [Indexed: 12/12/2022] Open
Abstract
Nucleos(t)ide analogue (Nuc) including entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide may suppress hepatitis B virus (HBV) DNA profoundly but have no direct action on covalently closed circular DNA, which is a very stable template for HBV production. Therefore, decades of long-term Nuc therapy are required to maintain HBV suppression and to achieve hepatitis B surface antigen (HBsAg) loss in hepatitis B e antigen (HBeAg)-negative patients. However, there are concerns including financial burden, adherence, and willingness for indefinite long-term Nuc therapy. Patients lost to follow-up and hence not monitored may risk severe relapse that may deteriorate to hepatic decompensation or even hepatic failure. Cessation of Nuc therapy in HBeAg-negative patients was initially considered in early 2000s. Earlier findings in Asian patients that finite Nuc therapy over 2-3 years is feasible and safe have founded Asian-Pacific Association for the Study of Liver stopping rule since 2008. Subsequent studies have confirmed the feasibility and safety of the strategy of finite Nuc therapy, which has finally been accepted as "an option" by American and European liver associations since 2016. More recent large studies since 2018 have further confirmed the pivotal finding of greatly increased HBsAg loss rate (~5-year 39%) after stopping Nuc therapy. With the high HBsAg loss rate as the main justification, the paradigm shift from indefinite long-term therapy to finite Nuc therapy in HBeAg-negative patients has been changing from an "option" to an "active recommendation" aiming to achieve HBsAg loss. More studies are needed to fine-tuning the strategy, including research for the optimal duration of consolidation therapy, timing to stop, and to start retreatment.
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Affiliation(s)
- Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
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Hirode G, Choi HSJ, Chen CH, Su TH, Seto WK, Van Hees S, Papatheodoridi M, Lens S, Wong G, Brakenhoff SM, Chien RN, Feld J, Sonneveld MJ, Chan HLY, Forns X, Papatheodoridis GV, Vanwolleghem T, Yuen MF, Hsu YC, Kao JH, Cornberg M, Hansen BE, Jeng WJ, Janssen HLA. Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study). Gastroenterology 2022; 162:757-771.e4. [PMID: 34762906 DOI: 10.1053/j.gastro.2021.11.002] [Citation(s) in RCA: 117] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB). METHODS This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)-negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation. RESULTS Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7-16.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; 95% confidence interval, 13.1-38.7; P < .001). At 48 months of follow-up, Whites with HBsAg levels <1000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a high predicted probability of HBsAg loss (>30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma. CONCLUSIONS The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.
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Affiliation(s)
- Grishma Hirode
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada
| | | | - Tung-Hung Su
- National Taiwan University Hospital, Taipei, Taiwan
| | - Wai-Kay Seto
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Stijn Van Hees
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | | | - Sabela Lens
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Grace Wong
- The Chinese University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Sylvia M Brakenhoff
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Jordan Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Henry L Y Chan
- The Chinese University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Xavier Forns
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | | | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Man-Fung Yuen
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Yao-Chun Hsu
- E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | | | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany Centre for Individualized Infection Medicine, Hannover, Germany
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada.
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Current Trend in Antiviral Therapy for Chronic Hepatitis B. Viruses 2022; 14:v14020434. [PMID: 35216027 PMCID: PMC8877417 DOI: 10.3390/v14020434] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/13/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.
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Chang ML, Liaw YF. Hepatitis B Flare in Hepatitis B e Antigen-Negative Patients: A Complicated Cascade of Innate and Adaptive Immune Responses. Int J Mol Sci 2022; 23:ijms23031552. [PMID: 35163476 PMCID: PMC8836007 DOI: 10.3390/ijms23031552] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/19/2022] [Accepted: 01/26/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a dynamic process involving interactions among HBV, hepatocytes, and the host immune system. The natural course of chronic hepatitis B (CHB) is divided into four chronological phases, including the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative phases. During HBV flare, alanine aminotransferase (ALT) levels abruptly rise to >5× the upper limit of normal; this is thought to occur due to the immune response against an upsurge in serum HBV DNA and antigen levels. Hepatitis flares may occur spontaneously, during or after antiviral therapy, or upon immunosuppression or chemotherapy in both HBeAg-positive and HBeAg-negative patients. The clinical spectrum of HBV flares varies from asymptomatic to hepatic decompensation or failure. HBeAg seroconversion with ≥ 1 year of consolidation therapy is accepted as an endpoint of oral antiviral therapy in HBeAg-positive patients, but recommendations for treating HBeAg-negative patients differ. Thus, the management of HBeAg-negative patients has attracted increasing interest. In the current review, we summarize various types of HBV flares and the associated complex cascade of innate and adaptive immune responses, with a focus on HBeAg-negative CHB patients. Hopefully, this review will provide insight into immunopathogenesis to improve the management of HBV flares in HBeAg-negative CHB patients.
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Affiliation(s)
- Ming-Ling Chang
- College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan;
- Division of Hepatology, Department of Hepatogastroenterology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
- Correspondence: ; Tel.: +886-3-3281200 (ext. 8107); Fax: +886-3-3272236
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan;
- Division of Hepatology, Department of Hepatogastroenterology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
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Neumann-Haefelin C, Thimme R. [Chronic hepatitis B virus infection: current and future treatment strategies]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2022; 65:238-245. [PMID: 35024895 PMCID: PMC8813712 DOI: 10.1007/s00103-021-03483-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/17/2021] [Indexed: 11/29/2022]
Abstract
Zur Therapie der chronischen Hepatitis-B-Virus-(HBV-)Infektion stehen aktuell pegyliertes Interferon-Alpha und Nucleosid‑/Nucleotidanaloga (Entecavir und Tenofovir) zur Verfügung. Diese Medikamente ermöglichen eine Virussuppression und eine Normalisierung des Leberenzyms Glutamat-Pyruvat-Transaminase (GPT) und verhindern ein Fortschreiten der Lebererkrankung. Zahlreiche noch in klinischer Entwicklung befindliche Therapiestrategien haben jedoch eine funktionelle Heilung zum Ziel. Dabei soll erreicht werden, dass das HBV-Hüllprotein HBsAg im Blutserum nicht mehr nachweisbar ist („ausgeheilte“ Hepatitis B). Der vorliegende Beitrag gibt eine Übersicht über aktuelle und mögliche zukünftige antivirale Therapien gegen die chronische HBV-Infektion. Als Grundlage diente eine Literaturrecherche unter besonderer Berücksichtigung der aktuellen Leitlinien sowie aktueller Kongressbeiträge. Die aktuell verfügbaren antiviralen Therapien führen nur sehr selten zur Elimination von HBsAg (funktionelle Heilung). Auch ist bisher weitgehend unklar, bei welchen Patienten ein Absetzen der Langzeittherapie mit Entecavir bzw. Tenofovir sinnvoll ist. Neue Therapiestrategien in klinischer Entwicklung führen bei einem höheren Anteil der Patienten zur funktionellen Heilung. Wahrscheinlich ist aber eine Kombination mehrerer antiviraler Strategien erforderlich, um die funktionelle Heilung für die Mehrheit der Patienten zu erreichen. Eine solche Therapie kann voraussichtlich in den nächsten 5–10 Jahren vorliegen.
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Affiliation(s)
- Christoph Neumann-Haefelin
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland
| | - Robert Thimme
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland.
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Reply to: Correspondence on 'the times they are a-changing - A refined proposal for finite HBV nucleos(t)ide analogue therapy.'. J Hepatol 2021; 75:1499-1501. [PMID: 34454996 DOI: 10.1016/j.jhep.2021.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 08/19/2021] [Indexed: 12/04/2022]
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Enomoto M, Umemura T, Suzuki F. I shall be released (from infinite HBV nucleos(t)ide analog therapy): Japanese experience. J Hepatol 2021; 75:1496-1497. [PMID: 34245805 DOI: 10.1016/j.jhep.2021.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/24/2021] [Accepted: 07/01/2021] [Indexed: 01/22/2023]
Affiliation(s)
- Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
| | - Takeji Umemura
- Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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Papatheodoridi M, Papatheodoridis G. New concepts regarding finite oral antiviral therapy for HBeAg-negative chronic hepatitis B. J Hepatol 2021; 75:1495-1496. [PMID: 34171438 DOI: 10.1016/j.jhep.2021.06.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 06/12/2021] [Indexed: 01/06/2023]
Affiliation(s)
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece.
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Jeng WJ, Chien RN, Liaw YF. Disputing issues in the paradigm change to finite antiviral therapy in HBeAg-negative patients. J Hepatol 2021; 75:1498-1499. [PMID: 34214616 DOI: 10.1016/j.jhep.2021.06.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/15/2021] [Accepted: 06/21/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan; College of Medicine, Chang Gung University, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan; College of Medicine, Chang Gung University, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan; College of Medicine, Chang Gung University, Taiwan.
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